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Cui Y, Li J, Zhao B, Liu J. Helicobacter pylori infection and inflammatory bowel disease: a 2-sample Mendelian randomization study. Front Microbiol 2024; 15:1384285. [PMID: 39498131 PMCID: PMC11533727 DOI: 10.3389/fmicb.2024.1384285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 10/07/2024] [Indexed: 11/07/2024] Open
Abstract
Introduction Observational studies have discovered a contradictory phenomenon between Helicobacter pylori (H. pylori) infection and inflammatory bowel disease (IBD). The study aimed to confirm the causal association between H. pylori and IBD, including ulcerative colitis (UC) and Crohn's disease (CD). Methods We conducted a Mendelian randomization (MR) study with two sample Genome-Wide Association Studies (GWAS) to determine whether there is a causal relationship between H. pylori infection and IBD, as well as the possible pathogenic factors that may be involved. The reliability of the main MR assumptions was examined through a series of sensitivity analyses. Results Two genetic variants (SNPs) previously identified were employed as instrumental variables (IVs) for H. pylori infection. GWAS data for IBD, UC, and CD were obtained from the recent DF10 release10 of the FinnGen study. Our findings indicated a significant association between H. pylori seropositivity and an increased risk of IBD and UC (IBD: OR: 1.16, 95% CI, 1.03-1.31, P < 0.05; UC: OR: 1.22, 95% CI, 1.08-1.37, P < 0.001) while no causal relationship with CD (P > 0.05). Analysis of the main virulence pathogenic factors revealed a causal relationship between cytotoxin-associated protein A (CagA) and IBD and UC (IBD: OR: 1. 06, 95% CI, 1.001-1.11, P < 0.05; UC: OR: 1.07, 95% CI, 1.004-1.14, P < 0.05), while no correlation was found for vacuolar cytotoxin A (VacA) (P > 0.05). After applying the False Discovery Rate (FDR) correction, the causal relationship between CagA and the risk of IBD or UC was no longer statistically significant. Conclusion This study suggests a potential causal relationship between H. pylori infection and IBD, particularly UC. The effect may be more pronounced in individuals with previous H. pylori infections.
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Affiliation(s)
- Yurong Cui
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Jinxin Li
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China
| | - Bing Zhao
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China
| | - Junying Liu
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
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Duryee MJ, Ahmad R, Eichele DD, Hunter CD, Mitra A, Talmon GA, Singh S, Smith LM, Rosen MJ, Dhawan P, Thiele GM, Singh AB. Identification of Immunoglobulin G Autoantibody Against Malondialdehyde-Acetaldehyde Adducts as a Novel Serological Biomarker for Ulcerative Colitis. Clin Transl Gastroenterol 2022; 13:e00469. [PMID: 35287144 PMCID: PMC9038499 DOI: 10.14309/ctg.0000000000000469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/06/2021] [Indexed: 12/01/2022] Open
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is associated with immune responses with oxidative stress wherein high levels of malondialdehyde result in the formation of a highly stable and immunogenic malondialdehyde-acetaldehyde adduct (MAA). Thus, this study evaluated the status of MAA and anti-MAA antibody isotypes in IBD and their potential as novel serological biomarkers for differentiating ulcerative colitis (UC) from Crohn's disease (CD). METHODS Levels of MAA and anti-MAA antibodies were examined in patients with IBD (171), non-IBD gastrointestinal diseases (77), and controls (83) from 2 independent cohorts using immunohistochemistry and enzyme-linked immunosorbent assay. Receiver operating characteristic curves and Youden cutoff index from logistic regression were used to determine the sensitivity and specificity. RESULTS The MAA and blood immunoglobulin G (IgG) anti-MAA antibody levels were significantly elevated in IBD compared with non-IBD patients (P = 0.0008) or controls (P = 0.02). Interestingly, patients with UC showed higher levels of IgG anti-MAA (P < 0.0001) than patients with CD including those with colonic CD (P = 0.0067). The odds ratio by logistic regression analysis predicted stronger association of IgG anti-MAA antibody with UC than CD. Subsequent analysis showed that IgG anti-MAA antibody levels could accurately identify (P = 0.0004) UC in the adult cohort with a sensitivity of 75.3% and a specificity of 71.4% and an area under the curve of 0.8072 (0.7121-0.9024). The pediatric cohort also showed an area under the curve of 0.8801 (0.7988-0.9614) and precisely distinguished (P < 0.0001) UC with sensitivity (95.8%) and specificity (72.3%). DISCUSSION Circulating IgG anti-MAA antibody levels can serve as a novel, noninvasive, and highly sensitive test to identify patients with UC and possibly differentiate them from patients with CD.
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Affiliation(s)
- Michael J. Duryee
- Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Derrick D. Eichele
- Division of Gastroenterology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Carlos D. Hunter
- Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Ananya Mitra
- Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Shailender Singh
- Division of Gastroenterology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Lynette M. Smith
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Michael J. Rosen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Geoffrey M. Thiele
- Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
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Majidova K, Handfield J, Kafi K, Martin RD, Kubinski R. Role of Digital Health and Artificial Intelligence in Inflammatory Bowel Disease: A Scoping Review. Genes (Basel) 2021; 12:1465. [PMID: 34680860 PMCID: PMC8535572 DOI: 10.3390/genes12101465] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD), subdivided into Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases that are characterized by relapsing and remitting periods of inflammation in the gastrointestinal tract. In recent years, the amount of research surrounding digital health (DH) and artificial intelligence (AI) has increased. The purpose of this scoping review is to explore this growing field of research to summarize the role of DH and AI in the diagnosis, treatment, monitoring and prognosis of IBD. A review of 21 articles revealed the impact of both AI algorithms and DH technologies; AI algorithms can improve diagnostic accuracy, assess disease activity, and predict treatment response based on data modalities such as endoscopic imaging and genetic data. In terms of DH, patients utilizing DH platforms experienced improvements in quality of life, disease literacy, treatment adherence, and medication management. In addition, DH methods can reduce the need for in-person appointments, decreasing the use of healthcare resources without compromising the standard of care. These articles demonstrate preliminary evidence of the potential of DH and AI for improving the management of IBD. However, the majority of these studies were performed in a regulated clinical environment. Therefore, further validation of these results in a real-world environment is required to assess the efficacy of these methods in the general IBD population.
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Affiliation(s)
| | | | | | | | - Ryszard Kubinski
- Phyla Technologies Inc., Montréal, QC H3C 4J9, Canada; (K.M.); (J.H.); (K.K.); (R.D.M.)
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Kuwada T, Shiokawa M, Kodama Y, Ota S, Kakiuchi N, Nannya Y, Yamazaki H, Yoshida H, Nakamura T, Matsumoto S, Muramoto Y, Yamamoto S, Honzawa Y, Kuriyama K, Okamoto K, Hirano T, Okada H, Marui S, Sogabe Y, Morita T, Matsumori T, Mima A, Nishikawa Y, Ueda T, Matsumura K, Uza N, Chiba T, Seno H. Identification of an Anti-Integrin αvβ6 Autoantibody in Patients With Ulcerative Colitis. Gastroenterology 2021; 160:2383-2394.e21. [PMID: 33582126 DOI: 10.1053/j.gastro.2021.02.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 01/12/2021] [Accepted: 02/09/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Ulcerative colitis is the most frequent type of inflammatory bowel disease and is characterized by colonic epithelial cell damage. Although involvement of autoimmunity has been suggested in ulcerative colitis, specific autoantigens/antibodies have yet to be elucidated. METHODS Using 23 recombinant integrin proteins, we performed enzyme-linked immunosorbent assays on sera from patients with ulcerative colitis and controls. Integrin expression and IgG binding in the colon tissues of patients with ulcerative colitis and controls were examined using immunofluorescence and coimmunoprecipitation, respectively. The blocking activity of autoantibodies was examined using solid-phase binding and cell adhesion assays. RESULTS Screening revealed that patients with ulcerative colitis had IgG antibodies against integrin αvβ6. In the training and validation groups, 103 of 112 (92.0%) patients with ulcerative colitis and only 8 of 155 (5.2%) controls had anti-integrin αvβ6 antibodies (P < .001), resulting in a sensitivity of 92.0% and a specificity of 94.8% for diagnosing ulcerative colitis. Anti-integrin αvβ6 antibody titers coincided with ulcerative colitis disease activity, and IgG1 was the major subclass. Patient IgG bound to the integrin αvβ6 expressed on colonic epithelial cells. Moreover, IgG of patients with ulcerative colitis blocked integrin αvβ6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif and inhibited cell adhesion. CONCLUSIONS A significant majority of patients with ulcerative colitis had autoantibodies against integrin αvβ6, which may serve as a potential diagnostic biomarker with high sensitivity and specificity.
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Affiliation(s)
- Takeshi Kuwada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masahiro Shiokawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Yuzo Kodama
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Sakiko Ota
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Yasuhito Nannya
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Hajime Yamazaki
- Department of Community Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Yoshida
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeharu Nakamura
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shimpei Matsumoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuya Muramoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shuji Yamamoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yusuke Honzawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Katsutoshi Kuriyama
- Department of Gastroenterology and Hepatology, Shiga General Hospital, Shiga, Japan
| | - Kanako Okamoto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomonori Hirano
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Okada
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Saiko Marui
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuko Sogabe
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Toshihiro Morita
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tomoaki Matsumori
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsushi Mima
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshihiro Nishikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tatsuki Ueda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazuyoshi Matsumura
- Department of Gastroenterology and Hepatology, Shiga General Hospital, Shiga, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Kansai Electric Power Hospital, Osaka, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Andreou NP, Legaki E, Gazouli M. Inflammatory bowel disease pathobiology: the role of the interferon signature. Ann Gastroenterol 2020; 33:125-133. [PMID: 32127733 PMCID: PMC7049232 DOI: 10.20524/aog.2020.0457] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/17/2019] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is still unclear, but includes both inflammatory and autoimmune reactions. Current methodological approaches could better elucidate the cytokine pathways and the genetics involved in the etiopathogenesis of this disease. Interferons (IFNs) are cytokines that play a key role in autoimmune/inflammatory disorders because of their pro- and anti-inflammatory properties as well as their immunoregulatory functions. An increased expression of IFN-regulated genes, widely known as an IFN signature, has been reported in blood and tissue from patients with autoimmune disorders. In this review, we present the function as well as the clinical and therapeutic potential of the IFN signature. Current data demonstrate that the IFN signature can be used as a biomarker that defines disease activity in autoimmune diseases, although this has not been thoroughly studied in IBD. Consequently, further investigation of the IFN signature in IBD would be essential for a better understanding of its actions.
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Affiliation(s)
- Nicolaos-Panagiotis Andreou
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelia Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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6
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Wang S, Fan T, Yao L, Ma R, Yang S, Yuan F. Circulating follicular regulatory T cells could inhibit Ig production in a CTLA-4-dependent manner but are dysregulated in ulcerative colitis. Mol Immunol 2019; 114:323-329. [PMID: 31442916 DOI: 10.1016/j.molimm.2019.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 08/05/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that occurs in the gastrointestinal tract, characterized by an upregulation in autoantibody production and antimicrobial antibody production. The interaction between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is critical to the induction and regulation of antibody production. In this study, we investigated the characteristics of Tfr cells in UC patients. We gated circulating Tfr cells as CD4+CXCR5+CD25+CD127- T cells, of which approximately 73% on average were Foxp3+. The circulating Tfh (CD4+CXCR5+CD25-) cells from control subjects and UC patients presented a comparable capacity to induce IgM production from naive B cells and to mediate class switching to IgG. Tfr cells significantly reduced Tfh-mediated B cell help in both healthy controls and UC patients in a concentration-dependent manner. However, the suppression capacity of Tfr cells was significantly lower in UC patients than in healthy controls. Subsequently, we found that the frequency of CTLA-4-expressing cells was only slightly lower in UC patients, but the MFI of CTLA-4, however, was markedly lower in UC patients. CTLA-4 blockade nearly abrogated Tfr-mediated suppression of IgM, and significantly reduced Tfr-mediated suppression of IgG. Moreover, CTLA-4 blockade removed the relative advantage of Tfr suppression capacity in healthy controls compared to UC patients. Overall, this study demonstrated that CTLA-4 was required for Tfr-mediated suppression of B cell help, but was expressed at lower levels in UC patients.
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Affiliation(s)
- Shaoxuan Wang
- Department of Gastroenterology, Jining First People's Hospital, Jining, Shandong, China.
| | - Tingting Fan
- Department of Gastroenterology, Jining First People's Hospital, Jining, Shandong, China
| | - Li Yao
- Department of Gastroenterology, Ningxia People's Hospital, Yinchuan, Ningxia, China.
| | - Ran Ma
- Department of Gastroenterology, Jining First People's Hospital, Jining, Shandong, China
| | - Shaofeng Yang
- Department of Gastroenterology, Jining First People's Hospital, Jining, Shandong, China
| | - Fang Yuan
- Department of Clinical Pharmacology, Jining First People's Hospital, Jining, Shandong, China
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7
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Castillo DF, Caicedo R, Gopalareddy V. Liver Abscess in a Pediatric Patient with Ulcerative Colitis: A Case Presentation. J Clin Transl Hepatol 2019; 7:93-96. [PMID: 30944825 PMCID: PMC6441647 DOI: 10.14218/jcth.2018.00045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 12/27/2018] [Accepted: 01/07/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatic abscesses are an uncommon extra-intestinal manifestation of inflammatory bowel disease, the incidence of which has been estimated to be approximately 7 per 10,000 patients with inflammatory bowel disease. It is unclear whether patients with Crohn's disease or patients with ulcerative colitis (UC) are at higher risk of developing this complication. Based on case reports, most cases are found in Crohn's disease; however, a recent cohort study showed an increased risk in UC instead. Hepatic abscesses in the pediatric population are rare, and there have been no reported cases of hepatic abscesses in a pediatric patient with UC. We describe herein a pediatric patient with UC who developed hepatic abscesses and portal vein thrombosis. This patient also had an extended time in remission from his UC despite being off of immunosuppressive therapies, and we speculate on how his clinical course and treatment strategies may have contributed to this.
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Affiliation(s)
- Daniel F. Castillo
- Department of Pediatrics, Atrium Health- Levine Children’s Hospital, Charlotte, NC, USA
- *Correspondence to: Daniel F. Castillo, Department of Pediatrics, Atrium Health- Levine Children’s Hospital, 1000 Blythe Blvd, Charlotte, NC 28203, USA. Tel: +1-407-314-5294, Fax: +1-704-381-6841, E-mail:
| | - Ricardo Caicedo
- Department of Pediatric Gastroenterology, Atrium Health- Levine Children’s Hospital, Charlotte, NC, USA
| | - Vani Gopalareddy
- Department of Pediatric Gastroenterology, Atrium Health- Levine Children’s Hospital, Charlotte, NC, USA
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8
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Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, Bueno SM. Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn's Disease and Ulcerative Colitis. Front Immunol 2018; 9:74. [PMID: 29441064 PMCID: PMC5797634 DOI: 10.3389/fimmu.2018.00074] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/11/2018] [Indexed: 01/06/2023] Open
Abstract
Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn’s disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC.
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Affiliation(s)
- Loni Berkowitz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bárbara M Schultz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Valentina P Sebastián
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel M Álvarez-Lobos
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev 2017; 16:416-426. [PMID: 28212924 DOI: 10.1016/j.autrev.2017.02.013] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.
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Affiliation(s)
- Jae Hyon Park
- Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Department of Paediatrics, Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, LU40DZ, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
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Abstract
IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.
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Affiliation(s)
- Heitor S P de Souza
- Department of Gastroenterology &Multidisciplinary Research Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil
| | - Claudio Fiocchi
- Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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11
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Pathogenesis, diagnosis, and management of ulcerative proctitis, chronic radiation proctopathy, and diversion proctitis. Inflamm Bowel Dis 2015; 21:703-15. [PMID: 25687266 DOI: 10.1097/mib.0000000000000227] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic proctitis refers to persistent or relapsing inflammation of the rectum, which results from a wide range of etiologies with various pathogenic mechanisms. The patients may share similar clinical presentations. Ulcerative proctitis, chronic radiation proctitis or proctopathy, and diversion proctitis are the 3 most common forms of chronic proctitis. Although the diagnosis of these disease entities may be straightforward in the most instances based on the clinical history, endoscopic, and histologic features, differential diagnosis may sometimes become problematic, especially when their etiologies and the disease processes overlap. The treatment for the 3 forms of chronic proctitis is different, which may shed some lights on their pathogenetic pathway. This article provides an overview of the latest data on the clinical features, etiologies, diagnosis, and management of ulcerative proctitis, chronic radiation proctopathy, and diversion proctitis.
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Zubaidi AM, Hussain T, Alzoghaibi MA. The time course of cytokine expressions plays a determining role in faster healing of intestinal and colonic anastomatic wounds. Saudi J Gastroenterol 2015; 21:412-7. [PMID: 26655138 PMCID: PMC4707811 DOI: 10.4103/1319-3767.170949] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Inflammation is critical in the early phases of wound healing. It has been reported previously that small intestinal and colonic wounds display a more rapid healing than those of other organs. However, the underlying mechanism has not yet been elucidated. Here we examined whether differences in the time course of specified cytokine expression, in colonic and small intestinal anastomotic lesions, might play a major role in this observation in comparison to lesions effecting skin and muscle tissue. MATERIALS AND METHODS Tissue lesions were applied to 36 male Sprague-Dawley rats. Tissue samples were harvested at 1, 3, 5, 7, and 14 days postoperatively with the levels of TNF-α, IL-6, and IFN-α determined by ELISA-derived methods. RESULTS The characteristics of TNF-α, IL-6, and IFN-α expression during the healing process for intestinal and colonic lesions were comparable. However, data differed significantly with that observed during healing of skin and muscle lesions. Intestinal and colonic lesions exhibited a significant and sustained increase in specified cytokine levels on day 5 to day 14 as compared with day 1 and 3. Skin and muscle lesions had random or unaltered cytokine levels throughout the study period. CONCLUSION Differences in expression of cytokines TNF-α, IL-6, and IFN-α indicate that these play an important role underlying the more rapid healing processes observed in small intestinal and colonic lesions.
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Affiliation(s)
- Ahmad M. Zubaidi
- Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Tajamul Hussain
- Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed A. Alzoghaibi
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia,Address for correspondence: Prof. Mohammed A. Alzoghaibi, Department of Physiology, College of Medicine, King Saud University, P.O. Box 2925 (29), Riyadh - 11641, Saudi Arabia. E-mail:
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Rana SV, Sharma S, Kaur J, Prasad KK, Sinha SK, Kochhar R, Malik A, Morya RK. Relationship of cytokines, oxidative stress and GI motility with bacterial overgrowth in ulcerative colitis patients. J Crohns Colitis 2014; 8:859-65. [PMID: 24456736 DOI: 10.1016/j.crohns.2014.01.007] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 01/08/2014] [Accepted: 01/08/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) is idiopathic, chronic and relapsing inflammatory bowel disease. Factors which initiate and perpetuate UC are not well understood. It is still unclear if any relationship exists between cytokines, oxidative stress, gastrointestinal (GI) motility, and small intestinal bacterial overgrowth (SIBO) in UC patients. GOALS To examine the relationship between these factors among UC patients. METHODS A total of 120 UC patients and 125 age and sex matched controls with no GI symptoms were enrolled. Plasma levels of IL-6, IL-8, TNF-α and IL-10 were measured in all subjects by using ELISA. Lipid peroxidation (LPO) and reduced glutathione (GSH) were measured by standard methods. Orocecal transit time (OCTT) and SIBO were measured by lactulose and glucose hydrogen breath tests respectively. RESULTS Out of the 120 UC patients, 74 were male with mean±SD age of 45.6±17.5years. Plasma levels of IL-6, IL-8, TNF-α and IL-10 in UC patients were significantly higher (p<0.01) as compared to controls. LPO in UC patients was significantly increased (p<0.01) while GSH was significantly decreased (p<0.01) as compared to controls. OCTT and SIBO were significantly higher in UC patients as compared to controls. UC patients with elevated inflammatory cytokines showed delayed OCTT and increased SIBO. It was also observed that there was a significant correlation between SIBO with IL-6, IL-8, TNF-α, and IL-10, LPO and GSH. CONCLUSION This study indicates that increase in cytokines and decrease in anti-oxidants in UC patients would have resulted in oxidative stress causing delayed GI motility leading to SIBO.
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Affiliation(s)
- Satya Vati Rana
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Surendra Sharma
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Jaspreet Kaur
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kaushal Kishore Prasad
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Saroj Kant Sinha
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rakesh Kochhar
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Aastha Malik
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rajesh Kumar Morya
- Department of Super Specialty of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Upregulation of the proinflammatory cytokine-induced neutrophil chemoattractant-1 and monocyte chemoattractant protein-1 in rats' intestinal anastomotic wound healing--does it matter? Asian J Surg 2013; 37:86-92. [PMID: 24060212 DOI: 10.1016/j.asjsur.2013.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 07/13/2013] [Accepted: 07/23/2013] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The proinflammatory cytokines and growth-promoting factor are essential components of the wound healing process. We hypothesized that under healthy conditions, faster healing of intestinal anastomotic wound is due to an early upregulation of proinflammatory cytokines, cytokine-induced neutrophil chemoattractant-1 (CINC-1) that is followed by a quicker upregulation of homeostatic chemokine, monocyte chemoattractant protein-1 (MCP-1) and late upregulation of transforming growth factor (TGF-β). METHODS We characterized the time course of CINC-1, MCP-1 and TGF-β release at four wounds (skin, muscle, small bowel, and colonic anastomosis) after surgery on 38 juvenile male Sprague Dawley rats. The tissue samples of each site were harvested at 0 (control), 1, 3, 5, 7 and 14 days postoperatively (n = 6-8/group) and analyzed by ELISA kits for CINC-1, MCP-1 and TGF-β. RESULTS CINC-1 expression peaked earlier in muscle and colonic wounds when compared to skin and small bowel. MCP-1 levels were elevated early in skin and muscle wounds, but later expression of MCP-1 was shown in colonic wounds. TGF-β levels were unchanged in all wound sites. CONCLUSION An earlier peak in CINC-1 levels and later expression of MCP-1 were seen in colonic wounds, but no significant increase in TGF-β levels was observed. These findings support the early healing process in intestinal anastomotic wounds.
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van de Ven AAJM, Hoytema van Konijnenburg DP, Wensing AMJ, van Montfrans JM. The role of prolonged viral gastrointestinal infections in the development of immunodeficiency-related enteropathy. Clin Rev Allergy Immunol 2012; 42:79-91. [PMID: 22116710 DOI: 10.1007/s12016-011-8292-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients with primary immunodeficiencies are prone to develop enteropathy of unknown pathogenesis. We hypothesize that ineffective clearance of gastrointestinal pathogens, particularly viruses, in combination with defective immune regulation may cause inflammatory enteropathy in certain immunodeficient hosts. We reviewed publications related to prolonged enteric viral infection, immunodeficiency, and the subsequent development of inflammatory enteropathy. Prolonged infection with especially enteroviral infections was reported more often in immunocompromised hosts than in healthy individuals. Protracted enteric viral shedding was not always associated with the presence or duration of gastrointestinal symptoms. The development of immunodeficiency-associated enteropathy after prolonged viral infections was described in sporadic cases. Clinical consequences of viral gut infections in immunocompromised hosts comprise isolation issues and supportive care. Prospective studies in cohorts of immunodeficient patients are required to study the impact of prolonged enteric viral replication with respect to the pathogenesis of non-infectious enteropathy.
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Affiliation(s)
- Annick A J M van de Ven
- Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, the Netherlands
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16
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Affiliation(s)
- Silvio Danese
- Department of Gastroenterology, Istituto Clinico Humanitas, Milan
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Antibody to tropomyosin isoform 5 and complement induce the lysis of colonocytes in ulcerative colitis. Am J Gastroenterol 2009; 104:2996-3003. [PMID: 19690525 DOI: 10.1038/ajg.2009.455] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Tropomyosins (TMs) are cytoskeletal microfilament proteins present in all eukaryotic cells. Human TM isoform 5 (hTM5) is the predominant isoform in colonic epithelial cells. Antibodies against hTM5 are found both in the sera and in the mucosa of patients with ulcerative colitis (UC) but not Crohn's disease (CD). We investigated whether anti-hTM5 autoantibodies are pathogenic. METHODS Normal-appearing colonic mucosal biopsy specimens were incubated with autologous serum. After 45 min, deposition of the complement component C3b was identified by indirect immunofluorescence assay (IFA). Additional specimens were incubated with autologous serum fixed in formalin, and their architecture was examined by hematoxylin and eosin (H&E) staining. RESULTS For 79% of UC patients, autologous serum caused C3b staining along the colonic epithelium. Recombinant hTM5 or anti-hTM5 monoclonal antibody blocked serum-induced C3b deposition. Immunoglobulin G (IgG) antibody and affinity-purified anti-hTM5 IgG antibody from UC sera with complement caused C3b deposition, indicating specificity of hTM5 as an autoantigen. When analyzed by H&E staining, sera obtained from 71% of UC patients caused a significant loss of epithelium. This process was inhibited by Fc fragments, indicating that it is complement mediated. With medium, normal, or CD serum, there was no C3b deposition or morphological changes of the colonic epithelium, indicating disease specificity. The ileal mucosa was not affected by UC sera, suggesting specificity for the colon. In UC mucosa, expression of hTM5 increased. CONCLUSIONS hTM5 acts as an autoantigen in UC. hTM5-specific IgG autoantibody in sera from UC patients induces C3b deposition and destruction of colonic epithelial cells, suggesting a direct pathogenic effect. If used as a diagnostic test to distinguish UC from CD, IFA would have 79% sensitivity and 100% specificity. Development of blocking antibodies may lead to novel therapies.
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Lanzoni G, Roda G, Belluzzi A, Roda E, Bagnara GP. Inflammatory bowel disease: Moving toward a stem cell-based therapy. World J Gastroenterol 2008. [PMID: 18698675 DOI: 10.3748/wjp.14.4616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.
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Affiliation(s)
- Giacomo Lanzoni
- Department of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, Bologna, Italy
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19
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Affiliation(s)
- Kiron M Das
- Division of Gastroenterology and Hepatology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Jersey, USA
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20
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Biancone L, Calabrese E, Palmieri G, Petruzziello C, Onali S, Sica GS, Cossignani M, Condino G, Das KM, Pallone F. Ileal lesions in patients with ulcerative colitis after ileo-rectal anastomosis: Relationship with colonic metaplasia. World J Gastroenterol 2008; 14:5290-300. [PMID: 18785281 PMCID: PMC2744059 DOI: 10.3748/wjg.14.5290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess whether in ulcerative colitis (UC) patients with ileo-rectal anastomosis (IRA), ileal lesions may develop in the neo-terminal-ileum and their possible relation with phenotypic changes towards colonic epithelium.
METHODS: A total of 19 patients with IRA under regular follow up were enrolled, including 11 UC and 8 controls (6 Crohn’s disease, CD; 1 familial adenomatous polyposis, FAP; 1 colon cancer, colon K). Ileal lesions were identified by ileoscopy with biopsies taken from the ileum (involved and uninvolved) and from the rectal stump. Staining included HE and immunohistochemistry using monoclonal antibodies against colonic epithelial protein CEP (Das-1) and human tropomyosin isoform 5, hTM5 (CG3). Possible relation between development of colonic metaplasia and ileal lesions was investigated.
RESULTS: Stenosing adenocarcinoma of the rectal stump was detected in 1 UC patient. The neo-terminal ileum was therefore investigated in 10/11 UC patients. Ileal ulcers were detected in 7/10 UC, associated with colonic metaplasia in 4/7 (57.1%) and Das-1 and CG3 reactivity in 3/4 UC. In controls, recurrence occurred in 4/6 CD, associated with colonic metaplasia in 3/4 and reactivity with Das-1 and CG3 in 2/3.
CONCLUSION: Present findings suggest that in UC, ileal lesions associated with changes towards colonic epithelium may develop also after IRA. Changes of the ileal content after colectomy may contribute to the development of colonic metaplasia, leading to ileal lesions both in the pouch and in the neo-terminal ileum after IRA.
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21
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Lanzoni G, Roda G, Belluzzi A, Roda E, Bagnara GP. Inflammatory bowel disease: Moving toward a stem cell-based therapy. World J Gastroenterol 2008; 14:4616-26. [PMID: 18698675 PMCID: PMC2738785 DOI: 10.3748/wjg.14.4616] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Revised: 07/09/2008] [Accepted: 07/16/2008] [Indexed: 02/06/2023] Open
Abstract
The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.
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22
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Yantiss RK, Das KM, Farraye FA, Odze RD. Alterations in the immunohistochemical expression of Das-1 and CG-3 in colonic mucosal biopsy specimens helps distinguish ulcerative colitis from Crohn disease and from other forms of colitis. Am J Surg Pathol 2008; 32:844-50. [PMID: 18408596 DOI: 10.1097/pas.0b013e31815b121c] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Distinction between ulcerative colitis (UC) and Crohn disease (CD) in mucosal biopsies is often difficult. Das-1 and CG-3 are monoclonal antibodies directed against an unknown colonic epithelial protein and human tropomyosin isoform-5, respectively, both show altered expression in patients with UC. In this study, we evaluated the utility of Das-1 and CG-3 in distinguishing UC from CD and from other types of colitis. One colonic biopsy specimen from each of 85 patients with confirmed UC (n=25), CD (n=15), lymphocytic (n=15), collagenous (n=15), and ischemic (n=15) colitis, and also 10 samples from normal controls, were stained for Das-1 and CG-3 using standard techniques. Reactivity for Das-1 and CG-3 was noted to be absent or present, and the location (ie, surface+/-crypt epithelium) and degree (weak or strong) of CG-3 staining was recorded. Loss of Das-1 staining occurred more frequently in UC (96%) compared with CD (20%), lymphocytic (20%), collagenous (13%), and ischemic colitis (0%) cases, as well as controls (10%, P<0.001 for all comparisons). CG-3 positivity in crypt epithelium was significantly more common in UC (52%) compared with the other groups (P< or =0.02 for all comparisons). The combination of strong crypt CG-3 staining and loss of Das-1 staining was noted in 44% of UC cases, but not in any other type of colitis (P=0.003 for all comparisons). We conclude that the patterns of Das-1 and CG-3 staining in colonic mucosal biopsies may be clinically useful in distinguishing UC from CD and from other colitidies.
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Affiliation(s)
- Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY,
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Simondi D, Mengozzi G, Betteto S, Bonardi R, Ghignone RP, Fagoonee S, Pellicano R, Sguazzini C, Pagni R, Rizzetto M, Astegiano M. Antiglycan antibodies as serological markers in the differential diagnosis of inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:645-51. [PMID: 18240283 DOI: 10.1002/ibd.20368] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The objective of the study was to evaluate the diagnostic accuracy of recently developed antiglycan serological tests in clinical practice for the diagnosis of Crohn's disease. METHODS This study was a cohort analysis of both clinical and biochemical parameters of patients with diagnosed inflammatory bowel disease compared with those in a control population. Antiglycan antibodies were determined using commercially available enzyme immunoassays. The setting was the outpatient unit of the gastroenterology department of a large, tertiary-care referral academic hospital. Participants were 214 consecutive patients, enrolled over a 5-month period, including 116 with Crohn's disease and 53 with ulcerative colitis, as well as 45 with other gastrointestinal diseases and 51 healthy controls. RESULTS Anti-Saccharomyces cerevisiae antibodies showed the best performance (54% sensitivity and 88%-95% specificity for Crohn's disease). Among patients with negative anti-Saccharomyces antibodies, 19 (34%) had high titers of at least another tested antiglycan antibody. Anti-Saccharomyces and anti-laminaribioside antibodies were associated with disease involving the small bowel and with penetrating or stricturing phenotype. Anti-laminaribioside was significantly higher in patients with a familial history of inflammatory bowel disease. CONCLUSIONS The new proposed serological markers are significantly associated with Crohn's disease, with low sensitivity but good specificity. About one third of anti-Saccharomyces-negative patients may be positive for at least 1 of those markers. Antiglycan antibodies appear to be associated with characteristic localization and phenotype of the disease.
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Affiliation(s)
- Daniele Simondi
- Department of Gastrohepatology, San Giovanni Battista Hospital of Turin, Turin, Italy
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Das KM, Bajpai M. Tropomyosins in human diseases: ulcerative colitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 644:158-67. [PMID: 19209821 DOI: 10.1007/978-0-387-85766-4_13] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Ulcerative colitis (UC) is a form of chronic inflammatory bowel disease (IBD) that almost always affects the rectal mucosa and variable length of the colon in continuity and at times mucosa of the entire colon. It is not caused by any specific pathogen. Genetics, environmental factors and altered immune responses to dietary macromolecules, colonic bacteria and cellular proteins have been implicated in the pathogenesis of UC. Autoimmune response against cytoskeletal, microfilament protein tropomyosin (Tm) seems to play an important role in the pathogenesis of UC. The predominant colonic epithelial Tm isoform, hTm5, can induce both humoral (B-cells) and cellular (T-cells) response in patients with UC. Such responses are not seen in normal subjects and disease control subjects, such as patients with Crohn's disease (CD, another type of IBD) and patients with lupus. A novel observation that hTm5 is expressed on colon epithelial cell surface but not on small intestinal epithelial cells provides evidence for presentation to immune effector cells. This surface expression of hTm5 seems to be facilitated by a colon epithelial cell membrane associated protein, CEP, that acts as a chaperone for the trans-migration of hTm5 to the surface and both hTm5 and CEP are then released outside the cell. Both CEP and hTm5 expression are increased with pro-inflammatory cytokine, such as gamma-interferon. hTm5 expression in UC mucosa is also significantly increased compared to normal. Finally, autoantibodies against hTm5 observed both in circulation and in the colon mucosa of patients with UC are pathogenic causing colon epithelial cell destruction by antibody and complement mediated cytolysis.
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Affiliation(s)
- Kiron M Das
- Division of Gastroenterology and Hepatology, Department of Medicine, Crohn's and Colitis Center of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
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Abstract
A modern approach to inflammatory bowel disease (IBD) research has been under way for little over one-half century, but only during the last two decades has progress accelerated and finally generated tangible results that have been translated into practical and better therapeutic strategies. The areas where progress has been more evident are those currently believed to be the key components of IBD pathogenesis, and include the environment, genetics, enteric microbiology, and immune reactivity. Progress in these different areas has been somewhat uneven, yielding a better understanding of the mechanisms behind gut inflammation and tissue injury rather than of specific etiological agents or predisposing factors. However, with the rapidly increasing utilization of novel methodological approaches like genetics, genomics, proteomics, and pharmacogenomics, it is reasonable to anticipate that the etiopathogenesis of IBD will be unveiled in the next couple of decades and more definitive, perhaps disease-modifying, approaches will be uncovered and implemented.
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Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Furuta R, Ando T, Watanabe O, Maeda O, Ishiguro K, Ina K, Kusugami K, Goto H. Rebamipide enema therapy as a treatment for patients with active distal ulcerative colitis. J Gastroenterol Hepatol 2007; 22:261-7. [PMID: 17295881 DOI: 10.1111/j.1440-1746.2006.04399.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The clinical efficacy of corticosteroids in the treatment of ulcerative colitis (UC) is well-established. However, prolonged usage of these drugs can result in serious complications. Rebamipide {2-(4-chlorobenzoylamino)-3[2-(1H)-quinolinon-4-yl] propionic acid}, a cytoprotective agent, has been reported to have anti-inflammatory activity and to repair mucosal injury in animal colitis models. The aim of the present study was to assess the clinical efficacy and safety of a novel Rebamipide enema therapy in UC patients. METHODS Twenty patients with the active distal type of UC in whom corticosteroid treatment had been unsuccessful were treated with rectal administration of Rebamipide twice a day for 3 weeks, during which corticosteroid dosage was kept constant. The efficacy of treatment was assessed from clinical symptoms and endoscopic findings. The anti-inflammatory effect of Rebamipide was also examined by monitoring changes in the intensity of histological inflammation and levels of cytokine activity in the rectal mucosa. RESULTS At 3 weeks after the initiation of Rebamipide enema therapy, 11 patients (55%) achieved clinical remission. Sixteen (80%) were colonoscopically judged to be responders, with decreased levels of interleukin (IL)-1beta but not of IL-8, and an increased ratio of IL-1 receptor antagonist/IL-1beta in organ cultures of mucosal tissues. The change in the number of infiltrating neutrophils was not significantly correlated with the clinical response to this therapy. No side-effects were noted in any patients. CONCLUSION Rebamipide enema therapy proved to be safe and useful in corticosteroid-refractory patients with the active distal type of UC.
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Affiliation(s)
- Ryuichi Furuta
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Ebert EC, Geng X, Lin J, Das KM. Autoantibodies against human tropomyosin isoform 5 in ulcerative colitis destroys colonic epithelial cells through antibody and complement-mediated lysis. Cell Immunol 2006; 244:43-9. [PMID: 17416356 DOI: 10.1016/j.cellimm.2007.02.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2006] [Revised: 02/09/2007] [Accepted: 02/11/2007] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Patients with ulcerative colitis (UC) have IgG1 antibodies in serum and colon against human tropomyosin isoform 5 (hTM5), a cytoskeletal microfilament protein found intracellularly and on the surface of colonic epithelial cells (EC). These antibodies may be pathogenic in UC. METHODS Sera from patients with UC (n=110) or Crohn's disease (CD) (n=50) and from healthy individuals (Hl) (n=30) were preincubated with recombinant hTM5 or bovine serum albumin (BSA), then cultured for 4h with (51)Cr-labelled colonic adenocarcinoma cells (LS180). Cytotoxicity was determined by (51)Cr release assay. RESULTS All serum samples lysed up to 36% of LS180 cells regardless of the source of the serum. However, adding hTM5 to UC, but not to CD or HI, sera reduced cytotoxicity by up to 75%. This hTM5-induced inhibition of cytotoxicity was found especially with sera from UC patients with active disease, and was found even after total colectomy. The hTM5-induced inhibition was mediated by purified IgG from UC sera. Complement was involved since hTM5-induced inhibition of cytotoxicity declined with either heat inactivation of the sera or premixing sera with Fc fragments. CONCLUSIONS This study shows that hTM5-specific IgG autoantibodies present in UC sera destroy LS180 cells by antibody and complement-mediated lysis. Such a phenomenon was not seen in CD or HI. This suggests an autoantigenic role of hTM5 and anti-hTM5 antibodies in the pathogenesis of UC. This observation may lead to novel diagnostic and therapeutic possibilities.
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Affiliation(s)
- Ellen C Ebert
- Crohn's and Colitis Center of NJ, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, 1 Robert Wood Johnson Place, MEB 478, New Brunswick, NJ 08903, USA.
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Mirza ZK, Sastri B, Lin JJC, Amenta PS, Das KM. Autoimmunity against human tropomyosin isoforms in ulcerative colitis: localization of specific human tropomyosin isoforms in the intestine and extraintestinal organs. Inflamm Bowel Dis 2006; 12:1036-43. [PMID: 17075344 DOI: 10.1097/01.mib.0000231573.65935.67] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Tropomyosins (TMs) are microfilament cytoskeletal proteins, and 5 major human TM isoforms (hTM1-5) are described. hTMs, particularly isoform 5 (hTM5), is capable of inducing autoantibodies and T-cell response in ulcerative colitis (UC). However, cellular localization of hTM isoforms in the colon and in extraintestinal organs commonly involved in UC is unknown. METHODS Using isoform-specific monoclonal antibodies, we localized hTMs through immunoperoxidase assay in normal colon (n = 12), small intestine (n = 14), esophagus (n = 10), skin (n = 19), eye (n = 12), gallbladder (n = 16), liver, including bile duct at the porta hepatis (n = 4), lungs (n = 4), and pancreas (n = 4). RESULTS There is intense expression of hTM5, but not other isoforms, in the epithelium of the colon, gallbladder, and skin. In the eye, hTM5 is expressed only in the nonpigmented ciliary epithelium. Although extrahepatic and interlobar large ductal biliary epithelium was positive, bile canaliculi at the portal tract are negative. The immunoreactivity in epithelial cells from these organs is diffuse cytoplasmic and along the periphery. In colon epithelium, there is intense expression along basolateral areas and luminal (apical) surface. In the small intestinal epithelium, however, hTM5 expression is weak and distinctly different than in the colon. hTM5 was not detected in the squamous epithelium of the esophagus, although it was strongly positive in the skin. hTM1, hTM2, and hTM3 are localized predominantly in smooth muscle of the intestine and blood vessel wall but not the epithelium. HTM4 is localized in the endothelial cells and basement membrane of the colonic epithelium. CONCLUSIONS hTM5 is the predominant isoform in the epithelium of colon and extraintestinal organs commonly involved in UC. The unique expression of hTM5 may allow its interaction with effector immune cells involved in the immunopathogenesis of UC and its extraintestinal manifestations.
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Affiliation(s)
- Zafar K Mirza
- Crohn's and Colitis Center of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick 08903, USA
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Abstract
Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn’s disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.
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Affiliation(s)
- Silvio Danese
- Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Milan, Italy
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30
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Zimmermann-Nielsen E, Grønbæk H, Dahlerup JF, Baatrup G, Thorlacius-Ussing O. Complement activation capacity in plasma before and during high-dose prednisolone treatment and tapering in exacerbations of Crohn's disease and ulcerative colitis. BMC Gastroenterol 2005; 5:31. [PMID: 16179087 PMCID: PMC1249564 DOI: 10.1186/1471-230x-5-31] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2005] [Accepted: 09/22/2005] [Indexed: 11/11/2022] Open
Abstract
Background Ulcerative colitis (UC) and Crohn's disease (CD) are characterized by intestinal inflammation mainly caused by a disturbance in the balance between cytokines and increased complement (C) activation. Our aim was to evaluate possible associations between C activation capacity and prednisolone treatment. Methods Plasma from patients with exacerbations of UC (n = 18) or CD (n = 18) were collected before and during high dose prednisolone treatment (1 mg/kg body weight) and tapering. Friedman's two way analysis of variance, Mann-Whitney U test and Wilcoxon signed-rank sum test were used Results Before treatment, plasma from CD patients showed significant elevations in all C-mediated analyses compared to the values obtained from 38 healthy controls (p < 0.02), and in mannan binding lectin (MBL)-concentration and MBL-C4-activation capacity (AC) values compared to UC patients (p < 0.02). Before treatment, plasma from UC patients showed significant elevations only in the classical pathway-mediated C3-AC compared to values obtained from healthy controls (p < 0.01). After treatment was initiated, significant reductions, which persisted during follow-up, were observed in the classical pathway-mediated C3-AC and MBL-C4-AC in plasma from CD patients (p < 0.05). Conclusion Our findings indicate that C activation capacity is up-regulated significantly in plasma from CD patients. The decreases observed after prednisolone treatment reflect a general down-regulation in immune activation.
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Affiliation(s)
- Erik Zimmermann-Nielsen
- Department of Surgery K, Hospital of Funen, Svendborg, Valdemarsgade 53, Denmark 5700 Svendborg
| | - Henning Grønbæk
- Department of Medicine V, Aarhus University Hospital, Nørrebrogade 44, Denmark 8000 Aarhus C
| | - Jens Frederik Dahlerup
- Department of Medicine V, Aarhus University Hospital, Nørrebrogade 44, Denmark 8000 Aarhus C
| | - Gunnar Baatrup
- Department of Surgical Gastroenterology, Haukeland University Hospital, Norway Bergen
| | - Ole Thorlacius-Ussing
- Department of Surgical Gastroenterology A, Aalborg Hospital, Hobrovej 18-22, Postbox 365, Denmark 9100 Aalborg
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31
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Repka JCD, Caron PE, Belila RT, Antunes MW, Campos Filho JTD, Bortolletto JV. Proposta de um novo modelo experimental de indução de doença inflamatória intestinal. Acta Cir Bras 2004. [DOI: 10.1590/s0102-86502004000500014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJETIVO: Avaliar as lesões intestinais em ratos imunizados com proteínas intestinais murinas. MÉTODOS: Preparou-se suspensão a 40% de cólon de ratos normais em PBS pH7,4, seguida de maceração, purificação, inativação e eletrofocalização de proteínas. Com esta suspensão 20 ratos Wistar foram imunizados conforme as seguintes fases: sensibilização via SC e IM com antígeno emulsificado em adjuvante completo de Freund. Reforços via IM com suspensão antigênica pura. Nesta fase foram pesquisados anticorpos séricos anti-tecido colônico por imunodifusão e face à positividade, dez ratos foram submetidos à avaliação histológica do cólon e em outros dez, inoculação via IP com suspensão antigênica pura. Após seis dias apresentaram: blefarite, diarréia, apatia, hematoquesia e então submetidos à coleta de amostras do cólon para avaliação histológica. RESULTADOS: A suspensão antigênica apresentou oito bandas de proteínas, entre 100 a 420 kD. Nas amostras de cólon observaram-se histologicamente perda de criptas, edema da camada sub-mucosa e inflamação aguda. CONCLUSÃO: Foi possível reproduzir doença inflamatória intestinal em ratos a partir de imunização com antígenos protéicos intestinais da própria espécie. A presença de anticorpos séricos anti-intestino foi relacionada com as alterações histológicas encontradas no cólon de ratos imunizados.
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32
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Kawamura T, Kanai T, Dohi T, Uraushihara K, Totsuka T, Iiyama R, Taneda C, Yamazaki M, Nakamura T, Higuchi T, Aiba Y, Tsubata T, Watanabe M. Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. THE JOURNAL OF IMMUNOLOGY 2004; 172:6388-97. [PMID: 15128830 DOI: 10.4049/jimmunol.172.10.6388] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Several studies indicate that CD4(+) T cells, macrophages, and dendritic cells initially mediate intestinal inflammation in murine models of human inflammatory bowel disease. However, the initial role of B cells in the development of intestinal inflammation remains unclear. In this study we present evidence that B cells can trigger intestinal inflammation using transgenic (Tg) mice expressing CD40 ligand (CD40L) ectopically on B cells (CD40L/B Tg). We demonstrated that CD40L/B Tg mice spontaneously developed severe transmural intestinal inflammation in both colon and ileum at 8-15 wk of age. In contrast, CD40L/B TgxCD40(-/-) double-mutant mice did not develop colitis, indicating the direct involvement of CD40-CD40L interaction in the development of intestinal inflammation. The inflammatory infiltrates consisted predominantly of massive aggregated, IgM-positive B cells. These mice were also characterized by the presence of anti-colon autoantibodies and elevated IFN-gamma production. Furthermore, although mice transferred with CD4(+) T cells alone or with both CD4(+) T and B220(+) B cells, but not B220(+) cells alone, from diseased CD40L/B Tg mice, develop colitis, mice transferred with B220(+) B cells from diseased CD40L/B Tg mice and CD4(+) T cells from wild-type mice also develop colitis, indicating that the Tg B cells should be a trigger for this colitis model, whereas T cells are involved as effectors. As it has been demonstrated that CD40L is ectopically expressed on B cells in some autoimmune diseases, the present study suggests the possible contribution of B cells in triggering intestinal inflammation in human inflammatory bowel disease.
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Affiliation(s)
- Takahiro Kawamura
- Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
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Abstract
Tolerance, the regulated inability to respond to a specific immunologic stimulant, is a physiological event important to normal immune function. Just as loss of tolerance to self-proteins results in autoimmune diseases, we assert that loss of tolerance to commensal flora in the intestinal lumen leads to inflammatory bowel disease (IBD). Mechanisms through which the mucosal immune system establishes and remains hyporesponsive toward the presence of food proteins and commensal flora, which we define as natural tolerance, are discussed. In addition to the contributions by commensal flora, the innate host defense and the adaptive immune systems promote natural tolerance to sustain normal mucosal homeostasis. Understanding the molecular and cellular events that mediate natural tolerance will lead to more advanced insights into IBD pathogenesis and improved therapeutic options.
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Affiliation(s)
- Robin L Jump
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA
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34
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Fukushima K, Fiocchi C. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol 2004; 286:G804-13. [PMID: 15068964 DOI: 10.1152/ajpgi.00398.2003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition.
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Affiliation(s)
- Kouhei Fukushima
- Div. of Gastroenterology, Univ. Hospitals of Cleveland, Case Western Reserve Univ. School of Medicine (BRB 425 10900 Euclid Ave., Cleveland, OH 44106-4952, USA
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35
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Fukushima K, Yonezawa H, Fiocchi C. Inflammatory bowel disease-associated gene expression in intestinal epithelial cells by differential cDNA screening and mRNA display. Inflamm Bowel Dis 2003; 9:290-301. [PMID: 14555912 DOI: 10.1097/00054725-200309000-00002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Intestinal epithelial cells are actively involved in the pathogenesis of inflammatory bowel disease resulting in an altered functional phenotype. The modulation of epithelial gene expression may occur as a consequence of proliferative, metabolic, immune, inflammatory, or genetic abnormalities. Differential screening of epithelial-cell-derived cDNA libraries (from control, ulcerative colitis, and Crohn's disease epithelial cells) and differential display of mRNA were used for investigation of disease-associated gene expression and modulation. Intestinal epithelial gene expression was successfully analyzed by both approaches. Using differential screening with clones encoding mitochondrial genes, quantitative overexpression was observed in both ulcerative colitis and Crohn's disease, while a unique expression of small RNA was noticed in Crohn's disease cells using Alu-homologous clones. Differential display demonstrated that several genes were differentially displayed among control, ulcerative colitis, and Crohn's disease epithelial cells. This was confirmed by immunohistochemical staining of pleckstrin, desmoglein 2 and voltage-dependent anion channel in control and inflammatory bowel disease mucosal samples. In summary, several inflammatory bowel disease-related associations were found. Since both differential screening and display have advantages and limitations, the combination of both techniques can generate complementary information, facilitate search for novel genes, and potentially identify genes uniquely associated with inflammatory bowel disease.
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Affiliation(s)
- Kouhei Fukushima
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
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36
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Nakamura H, Yoshida K, Ikegame K, Kishima Y, Uyama H, Enomoto H. Antibodies against hepatoma-derived growth factor and mucosal repair in ulcerative colitis. J Gastroenterol 2002; 37 Suppl 14:8-14. [PMID: 12572860 DOI: 10.1007/bf03326407] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Ulcerative colitis is a chronic inflammatory disease of colonic mucosa in which the pathogenesis of any immunological disorders would likely be related. Various circulating autoantibodies have been reported in patients with ulcerative colitis, although their possible roles in this disease process have not yet been clarified. Autoantibody against hepatoma-derived growth factor (HDGF) was detected at high frequency in the serum of patients with ulcerative colitis, especially in patients with total colitis and left-sided colitis. In pursuit of the possible role of anti-HDGF autoantibody in the pathogenesis, we investigated HDGF expression in the intestinal mucosa by Western blotting and immunohistochemistry and the effects of recombinant proteins and antirecombinant HDGF antibody on the proliferation of the colonic epithelial cell-derived cell line, HT-29. HDGF was expressed in the nucleus of the colonic epithelial cells dominantly in the bottom of the crypts. Recombinant HDGF stimulated the proliferation of HT-29 cells significantly, although its effects were small, about 20% greater than the control at 100 ng/ml. On the other hand, the polyclonal IgG antibody against recombinant HDGF generated by rabbits suppressed their proliferation almost completely at 250 microg/ml. These findings suggest that HDGF plays an important role in epithelial cell renewal of intestinal crypts as a growth and survival factor, and that autoantibody against HDGF may delay mucosal healing and repair by inhibiting the stimulatory effects of HDGF on epithelial cell proliferation, resulting in a chronic process of colonic mucosal injury.
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Affiliation(s)
- Hideji Nakamura
- Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan
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37
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Biancone L, Monteleone I, Del Vecchio Blanco G, Vavassori P, Pallone F. Resident bacterial flora and immune system. Dig Liver Dis 2002; 34 Suppl 2:S37-43. [PMID: 12408438 DOI: 10.1016/s1590-8658(02)80162-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The "controlled inflammation" of the normal human gut is a closely controlled phenomenon and any change in the cell type number and/or functions, including the release of soluble mediators can lead to an "uncontrolled" inflammation. The physiological inflammation in the human gut plays a crucial role in maintaining a local immune response that is appropriate, efficiently protective and which respects the gut structure and function. The intestinal mucosa represents a considerable proportion of the human immune system. Disregulation of the mucosal immune response can switch a "controlled" toward an "uncontrolled" intestinal inflammation. A key role in the maintenance of an adequate balance between antigenic stimulation and host immune response is played by the immunoregulatory molecules released by activated immunocytes in the human gut. The role of the host immune system in the maintenance of an adequate balance between luminal antigens, including the resident bacterial flora and host immune response, is strongly supported by animal models of uncontrolled intestinal inflammation. Besides the aetiology of inflammatory bowel disease, luminal antigens (including food, viral and bacterial antigens) contribute to the maintenance of the inflammatory process in inflammatory bowel disease, by stimulating the immunocompetent cells in the intestinal mucosa. Of the luminal antigens, the resident bacterial flora seems to play a major role in the development of animal models of "uncontrolled" intestinal inflammation. Recent evidence also suggest that bacterial flora can modulate the function of the intestinal mucosal cells. These observations support the role of the intestinal bacterial flora in the induction of an uncontrolled inflammation in the human gut, leading to tissue damage. Probiotics, defined as living micro-organisms which, when taken in appropriate amounts, improve the health status, have been proposed in the treatment of inflammatory bowel disease, but their mechanisms of action still remain to be fully elucidated.
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Affiliation(s)
- L Biancone
- Gastroenterology Unit, Department of Internal Medicine, University of Rome Tor Vergata, Italy.
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38
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Oshitani N, Hato F, Jinno Y, Sawa Y, Hara J, Nakamura S, Matsumoto T, Arakawa T, Kitano A, Kitagawa S, Kuroki T. Heterogeneity of HPLC profiles of human class II MHC-bound peptides isolated from intestine with inflammatory bowel disease. Dig Dis Sci 2002; 47:2088-94. [PMID: 12353860 DOI: 10.1023/a:1019689332601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Studies of the T-cell-receptor repertoire and oligoclonal expansion of lamina propria T cells in patients with Crohn's disease suggest restricted antigen processing in this disease. We examined HPLC elution profiles of HLA-DR-bound peptides isolated from human intestine. Surgical samples of colon and ileum were obtained from patients with ulcerative colitis, patients with Crohn's disease, and normal colon from patients undergoing colon carcinoma treatment as controls. Specimens were homogenized and HLA-DR molecules were isolated using anti-HLA-DR antibody-coupled immunoaffinity chromatography. HLA-DR-bound peptides were dissociated from the HLA-DR groove by acid treatment, isolated, and analyzed by reversed-phase HPLC. HPLC elution profiles of HLA-DR-bound peptides were similar in patients with ulcerative colitis and controls. Large peaks were found in patients with Crohn's disease, but the retention times of these peaks differed among individuals. Elution profiles of HLA-DR bound peptides suggest that specific antigen presentation might occur in patients with Crohn's disease, although the specific antigens appear to differ between patients.
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Affiliation(s)
- Nobuhide Oshitani
- Third Department of Internal Medicine, Osaka City University Medical School, Japan
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39
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Oliva-Hemker M, Fiocchi C. Etiopathogenesis of inflammatory bowel disease: the importance of the pediatric perspective. Inflamm Bowel Dis 2002; 8:112-28. [PMID: 11854610 DOI: 10.1097/00054725-200203000-00008] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD) is now recognized as a common chronic disease affecting children and adolescents. This article will review recent advances made in the fields of genetics, epidemiology, gut ecology, and immunology regarding the etiopathogenesis of IBD, with particular emphasis on the contributions made by pediatric studies. Areas where further study of the pediatric age group would be beneficial will be highlighted.
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Affiliation(s)
- Maria Oliva-Hemker
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Brady 320, 600 N. Wolfe St., Baltimore, MD 21287-2631, USA.
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40
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Abstract
Ulcerative colitis is a chronic inflammatory disease of the rectum and colon. Results from many studies in people and animals of intestinal inflammation suggest that ulcerative colitis results from environmental factors triggering a loss of tolerance for normal intestinal flora in genetically susceptible individuals. Although progress has been made in the overall management of the disease, no innovative treatment has been developed. By contrast with Crohn's disease, there are few clinical data on biological agents. Probiotics seem the most promising of several experimental and traditional agents that have been investigated in controlled clinical trials.
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Affiliation(s)
- Richard J Farrell
- Division of Gastroenterology, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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41
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Shlomai A, Trop S, Gotsman I, Jurim O, Diment J, Alper R, Rabbani E, Engelhardt D, Ilan Y. Immunomodulation of experimental colitis: the role of NK1.1 liver lymphocytes and surrogate antigens--bystander effect. J Pathol 2001; 195:498-507. [PMID: 11745683 DOI: 10.1002/path.974] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The imbalance between Th1 pro-inflammatory and Th2 anti-inflammatory cytokine-producing cells plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Induction of oral tolerance to colitis-extracted proteins was previously shown to down-regulate the anti-colon immune response, thereby alleviating experimental colitis. Immune bystander effect and liver-associated lymphocytes expressing the NK1.1 marker (NK1.1(+) LAL) have been suggested as being important in tolerance induction. The aims of the present study were to determine whether oral administration of inflammatory and non-inflammatory colon-extracted proteins of different species can induce peripheral immune tolerance and alleviate experimental colitis; and to examine the role of NK1.1(+) LAL in oral tolerance induction. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzene sulphonic acid (TNBS). Mice received six oral doses of colonic proteins extracted from TNBS-colitis colonic wall, or normal colonic wall, from four different species. Standard clinical, macroscopic, and microscopic scores were used for colitis assessment. Serum interferon gamma (IFNgamma) and interleukin 10 (IL10) levels were measured by ELISA. To evaluate the role of NK1.1(+) LAL in maintaining the balance between immunogenic and tolerogenic subsets of cells, their cytotoxicity functions were tested in tolerized and non-tolerized-mice. The administration of mouse-derived colitis-extracted proteins, or of surrogate proteins extracted from normal mouse colon, or from rat or human inflammatory colons, was found to alleviate experimental colitis. Tolerized mice had less diarrhoea; showed a marked reduction of colonic ulceration, intestinal and peritoneal adhesions, wall thickness, and oedema; and demonstrated a significant improvement of all microscopic parameters for colitis. Induction of tolerance led to an increase in IL10 and a decrease in IFNgamma serum levels. NK1.1(+) LAL cytotoxicity function increased markedly in tolerized mice. In contrast, mice fed with proteins extracted from normal rat, rabbit, and human colon, or from rabbit inflammatory colon, developed severe colitis, with a marked increase in IFNgamma and a decrease in IL10 serum levels, and down-regulation of NK1.1(+) LAL function. This study has shown that oral tolerance can be induced in experimental colitis by means of the feeding of surrogate antigens; this alleviates experimental colitis. NK1.1(+) LAL cytotoxicity function is associated with peripheral tolerance induction and may help to maintain the Th1/Th2 immune balance.
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Affiliation(s)
- A Shlomai
- Liver Unit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel
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42
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Dasgupta A, Ramaswamy K, Giraldo J, Taniguchi M, Amenta PS, Das KM. Colon epithelial cellular protein induces oral tolerance in the experimental model of colitis by trinitrobenzene sulfonic acid. THE JOURNAL OF LABORATORY AND CLINICAL MEDICINE 2001; 138:257-69. [PMID: 11574820 DOI: 10.1067/mlc.2001.118221] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Rectal administration of trinitrobenzene sulfonic acid (TNBS) produces chronic colitis in experimental animals. However, the role of epithelial cellular protein(s) in this model is unknown. We examined whether oral tolerance can be induced in this model with colon epithelial cell proteins and whether it is organ specific. Rats were fed five times with extracts of LS-180 human colon cancer cells or HT 1080 human fibroblast cells. Syngeneic normal rat colon or small intestinal extracts were fed to separate groups of rats. After oral feedings, each rat received TNBS by enema. Rats were killed 15 days later, and the following were measured: gross and histologic disease score, weight, thickness, and myeloperoxidase values of colon and serum interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels. Rectal TNBS alone produced severe colitis with a 26% mortality rate. Rats fed LS-180 or rat colon extract before TNBS enema were protected, as evidenced by reductions in mortality rate, disease scores, and myeloperoxidase values. However, rats fed HT 1080 or small intestine extract lacked such protection. To examine the possible mechanism of the oral tolerance, T lymphocytes from mesenteric lymph nodes and spleen of LS-180 extract-fed rats were passively transferred to naive rats, and this was followed by TNBS enema. These rats showed clear protection. Protected animals had low IFN-gamma and high TGF-beta levels. This study demonstrates that cellular protein(s) from human colon epithelial cells, but not from human fibroblasts, can induce oral tolerance in experimental colitis. This oral tolerance is mediated by primed mesenteric and splenic T lymphocytes.
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Affiliation(s)
- A Dasgupta
- Crohn's and Colitis Center of New Jersey, Division of Gastroenterology and Hepatology, Department of Medicine, New Brunswick, NJ, USA
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43
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Abstract
Crohn disease and ulcerative colitis are caused by an excessive immune-inflammatory reaction in the intestinal wall. Analysis of the types of immune response ongoing in the inflamed intestine has revealed that in Crohn disease there is predominantly a T helper cell type 1 response, with exaggerated production of interleukin (IL)-12 and interferon-gamma, whereas in ulcerative colitis the lesion seems to be more of an antibody-mediated hypersensitivity reaction. Despite these differences, downstream inflammatory events are probably similar in both conditions. In both Crohn disease and ulcerative colitis there is an increased synthesis of proinflammatory cytokines, including IL-1beta, IL-6, IL-8, IL-16, and tumor necrosis factor-alpha accompanying the influx of nonspecific inflammatory cells into the mucosa. These cytokines contribute to the tissue damage either directly or indirectly by enhancing the production of matrix metalloproteinases and growth factors, which produce ulceration as well as mucosal repair.
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Affiliation(s)
- F Pallone
- Department of Internal Medicine, Universita' di Roma Tor Vergata, Rome, Italy.
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44
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Abstract
The last decade has seen tremendous advances in our knowledge, which has led to genuine improvements in our understanding of the pathogenesis and management of inflammatory bowel disease (IBD). The combined power of cellular and molecular biology has begun to unveil the enigmas of IBD, and, consequently, substantial gains have been made in the treatment of IBD. Refinements in drug formulation have provided the ability to target distinct sites of delivery, while enhancing the safety and efficacy of older agents. Simultaneous progress in biotechnology has fostered the development of new agents that strategically target pivotal processes in disease pathogenesis. This article addresses our current understanding of the pathogenesis of IBD, including the latest developments in animal models and covers agents currently used in the treatment of IBD as well as emerging therapies.
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Affiliation(s)
- R J Farrell
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA
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Gasche C, Bakos S, Dejaco C, Tillinger W, Zakeri S, Reinisch W. IL-10 secretion and sensitivity in normal human intestine and inflammatory bowel disease. J Clin Immunol 2000; 20:362-70. [PMID: 11051278 DOI: 10.1023/a:1006672114184] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Interleukin-10 (IL-10) deficiency in gene knockout mice causes chronic enterocolitis. We hypothesized that inflammation in human inflammatory bowel disease might result from innate alterations in the IL-10 pathway. Serum, supernatants, and mRNA of peripheral blood mononuclear cells (PBMC) and lamina propria mononuclear cells (LPMC) derived from inflamed (LPMC-i) and noninflamed colonic mucosa (LPMC-ni) were collected from patients with Crohn's colitis, ulcerative colitis, and controls. IL-10 protein concentrations and IL-10 mRNA were examined in response to PMA/CD3 or PHA stimulation. The response to rhIL-10 was assessed by inhibition of tumor necrosis factor-alpha (TNF-alpha), IL-6, and interferon-gamma (IFN-gamma) production. Serum IL-10 levels of inflammatory bowel disease (IBD) patients were within the normal range. IL-10 concentrations in supernatants from LPMC-i were significantly lower than from LPMC-ni or PBMC. No difference was seen between samples from ulcerative colitis and Crohn's disease. IL-10 mRNA was detected in 0/4 LPMC-i samples compared to 1/6 LPMC-ni and 6/6 PBMC. RhIL-10 inhibited TNF-alpha, IL-6, and IFN-gamma synthesis in PBMC. This effect was strongly diminished in LPMC. Disease-specific alterations were not detected. Our data suggest that LPMC derived from inflamed colonic mucosa have a reduced ability to produce and to respond to rhIL-10. A disease-specific alteration in the IL-10 pathway, however, was not found.
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Affiliation(s)
- C Gasche
- Department of Gastroenterology and Hepatology, University of Vienna, Austria.
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Onuma EK, Amenta PS, Ramaswamy K, Lin JJ, Das KM. Autoimmunity in ulcerative colitis (UC): a predominant colonic mucosal B cell response against human tropomyosin isoform 5. Clin Exp Immunol 2000; 121:466-71. [PMID: 10971512 PMCID: PMC1905719 DOI: 10.1046/j.1365-2249.2000.01330.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We set out to examine if the IgG-producing cells in the colonic mucosa in UC are committed to tropomyosin isoform 5 (hTM5), a putative autoantigen in UC. Lamina propria mononuclear cells (LPMC) were isolated from colonoscopic biopsy specimens from recto-sigmoid and proximal colon. Twenty-three patients with UC, eight with Crohn's colitis (CC), and 10 non-inflammatory bowel disease (non-IBD) controls were included. The ELISPOT assays were used to quantify lamina propria B cells producing total immunoglobulin (IgA, IgG, IgM), IgG, IgA, as well as IgG against hTM5 isoform. The median value of percentage of total IgG-producing lymphocytes was similar in UC (12%) and CC (11%), but was significantly (P < 0.0002) higher than non-IBD controls (6%). However, in UC, but not in CC and non-IBD, a large number of lamina propria B cells produced IgG against hTM5 (median values: UC 42%, CC 2.5%, non-IBD 0%). This difference in UC when compared with CC and non-IBD was highly significant (P < 0.00001). Twenty-one of 23 (91%) patients with UC had percentage of anti-hTM5 IgG-producing immunocytes more than 2 s. d. above the mean for non-UC patients. In UC but not in CC and non-IBD controls, the increased number of IgG-producing cells are largely committed to produce IgG against hTM5-related epitope(s).
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Affiliation(s)
- E K Onuma
- Division of Gastroenterology and Hepatology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
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47
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Sakamaki S, Takayanagi N, Yoshizaki N, Hayashi S, Takayama T, Kato J, Kogawa K, Yamauchi N, Takemoto N, Nobuoka A, Ayabe T, Kohgo Y, Niitsu Y. Autoantibodies against the specific epitope of human tropomyosin(s) detected by a peptide based enzyme immunoassay in sera of patients with ulcerative colitis show antibody dependent cell mediated cytotoxicity against HLA-DPw9 transfected L cells. Gut 2000; 47:236-41. [PMID: 10896915 PMCID: PMC1727987 DOI: 10.1136/gut.47.2.236] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Recent studies suggest that tropomyosin (TM) may act as a putative autoantigen in ulcerative colitis (UC). Recently, we identified, by computer homology analysis, a specific peptide (HIAEDADRK) in human TM that can bind to HLA-DPw9. The aim of this study was to investigate the presence of autoantibodies against this peptide in UC. METHODS Antibodies were measured by ELISA with a synthetic peptide in 20 healthy volunteers, 48 patients with UC, 26 with Crohn's disease (CD), eight with primary sclerosing cholangitis (PSC), and six with primary biliary cirrhosis (PBC). The functional significance of antibodies was investigated by antibody dependent cell mediated cytotoxicity (ADCC) against DPw9 transfected L cells using a standard (51)Cr release assay. RESULTS Optical density values (mean (SD)) of sera from patients with UC (1.40 (0. 52)) and PSC (1.65 (0.12)) were significantly higher than those from healthy volunteers (0.32 (0.28)) (p<0.05), CD (0.50 (0.34)) (p<0.05) and PBC (0.14 (0.09)) (p<0.05). Values in UC decreased with clinical improvement. The ADCC activity of UC sera correlated well with antibody titre against this synthetic peptide. CONCLUSIONS Anti-TM antibody was detected in UC sera by a specific peptide based ELISA with high reproducibility. This peptide may be an antigenic epitope of TM involved in the immunopathogenesis of UC and, perhaps, PSC.
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Affiliation(s)
- S Sakamaki
- 4th Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan
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48
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Yeung MM, Melgar S, Baranov V, Oberg A, Danielsson A, Hammarström S, Hammarström ML. Characterisation of mucosal lymphoid aggregates in ulcerative colitis: immune cell phenotype and TcR-gammadelta expression. Gut 2000; 47:215-27. [PMID: 10896913 PMCID: PMC1728017 DOI: 10.1136/gut.47.2.215] [Citation(s) in RCA: 110] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS A histopathological feature considered indicative of ulcerative colitis (UC) is the so-called basal lymphoid aggregates. Their relevance in the pathogenesis of UC is, however, unknown. We have performed a comprehensive analysis of the immune cells in these aggregates most likely corresponding to the lymphoid follicular hyperplasia also described in other colitides. METHODS Resection specimens of UC and normal colon were analysed by immunomorphometry, immunoflow cytometry, and immunoelectron microscopy, using a large panel of monoclonal antibodies. RESULTS (1) In all cases of UC, colonic lamina propria contained numerous basal aggregates composed of lymphocytes, follicular dendritic cells, and CD80/B7.1 positive dendritic cells. (2) CD4(+)CD28(-) alphabeta T cells and B cells were the dominant cell types in the aggregates. (3) The aggregates contained a large fraction of cells that are normally associated with the epithelium: that is, gammadelta T cells (11 (7)%) and alpha(E)beta(7)(+) cells (26 (13)%). The gammadelta T cells used Vdelta1 and were CD4(-)CD8(-). Immunoelectron microscopy analysis demonstrated TcR-gammadelta internalisation and surface downregulation, indicating that the gammadelta T cells were activated and engaged in the disease process. (4) One third of cells in the aggregates expressed the antiapoptotic protein bcl-2. CONCLUSIONS Basal lymphoid aggregates in UC colon are a consequence of anomalous lymphoid follicular hyperplasia, characterised by abnormal follicular architecture and unusual cell immunophenotypes. The aggregates increase in size with severity of disease, and contain large numbers of apoptosis resistant cells and activated mucosal gammadelta T cells. The latter probably colonise the aggregates as an immunoregulatory response to stressed lymphocytes or as a substitute for defective T helper cells in B cell activation. gammadelta T cells in the aggregates may be characteristic of UC.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- B-Lymphocytes/cytology
- B-Lymphocytes/immunology
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/pathology
- Dendritic Cells, Follicular/cytology
- Down-Regulation
- Female
- Flow Cytometry
- Gene Expression Regulation
- Genes, T-Cell Receptor delta/genetics
- Genes, bcl-2
- Humans
- Immunity, Cellular
- Immunophenotyping
- Male
- Microscopy, Electron
- Middle Aged
- Phenotype
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Lymphocyte Homing/genetics
- T-Lymphocytes/cytology
- T-Lymphocytes/immunology
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Affiliation(s)
- M M Yeung
- Department of Immunology, Umeå University, Sweden
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49
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Matsuura T, West GA, Levine AD, Fiocchi C. Selective resistance of mucosal T-cell activation to immunosuppression in Crohn's disease. Dig Liver Dis 2000; 32:484-94. [PMID: 11057923 DOI: 10.1016/s1590-8658(00)80005-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS The inappropriately high state of T-cell activation found in Crohn's disease could be due to failure to respond to inhibitory signals. We tested the hypothesis that Crohn's disease mucosal T-cells are resistant to the immunosuppressive action of interleukin4. PATIENTS Patients with Crohn's disease, ulcerative colitis, and other malignant and non-malignant conditions undergoing bowel resection. METHODS The effect of interleukin-4 on lamina propria mononuclear cells from Crohn's disease, ulcerative colitis and control mucosa was assessed on various T-cell functions: interleukin-2-induced cytotoxicity, soluble interleukin-2 receptor and interleukin-2 production, and expression of mRNA for interleukin-2R and interferon-gamma. RESULTS Cytotoxicity of control and ulcerative colitis cells was markedly decreased by interleukin-4, whereas Crohn's disease cells failed to be inhibited. Addition of interleukin-4 to interleukin-2-stimulated cultures decreased soluble interleukin-2R production significantly less in Crohn's disease and ulcerative colitis than control cells. In the same cultures, residual levels of interleukin-2 were significantly increased in control and ulcerative colitis, but not Crohn's disease cultures. Finally, Crohn's disease cells were significantly more resistant to interleukin-4-mediated inhibition of spontaneous and interleukin-2-induced expression of interleukin-2Ralpha and interferon-gamma mRNA compared to control cells. CONCLUSIONS The effector function, receptor expression and cytokine production of Crohn's disease mucosal T-cells are resistant to interleukin4-mediated inhibition. Failure to respond to down-regulatory signals may contribute to persistent T-cell activation and chronicity of inflammation in Crohn's disease.
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Affiliation(s)
- T Matsuura
- Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University, School of Medicine, OH 44106-4952, USA
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50
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Ilan Y, Weksler-Zangen S, Ben-Horin S, Diment J, Sauter B, Rabbani E, Engelhardt D, Chowdhury NR, Chowdhury JR, Goldin E. Treatment of experimental colitis by oral tolerance induction: a central role for suppressor lymphocytes. Am J Gastroenterol 2000; 95:966-73. [PMID: 10763946 DOI: 10.1111/j.1572-0241.2000.01935.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Inflammatory bowel diseases (IBD) are immune-mediated disorders wherein an imbalance between proinflammatory (Th1) and antiinflammatory (Th2) cytokines is thought to play a role in the pathogenesis. The aim of this study was to test whether induction of oral tolerance to proteins extracted from inflammatory colon alleviates experimental colitis, and whether oral tolerization mediated by suppressor cells can induce immune tolerance. METHODS Colitis was induced in rats by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Rats received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall. Splenocytes harvested from tolerized and control rats were transplanted into irradiated naive rats. RESULTS Feeding of colitis-extracted proteins ameliorated colonic inflammation, as shown by reduction of colonic ulcerations, as well as decreased diarrhea, intestine and peritoneal adhesions, wall thickness, and edema. A marked reduction of the fraction of injured colonic area and colon weight, and decrease in colon weight, were observed in tolerized rats versus controls. Histological parameters for colitis were markedly improved in tolerized animals that showed significant reduction in inflammatory response and mucosal ulcerations. Tolerized rats developed an increase in TGFbeta1 and a decrease in IFNgamma serum levels. TNBS-induced colitis was significantly attenuated in naive recipients of splenocytes from tolerized rats, compared with rats that received splenocytes from control donors. CONCLUSIONS Induction of oral tolerance to colitis-extracted proteins downregulates the anticolon immune response, thereby ameliorating experimental colitis. Suppressor lymphocytes mediate the tolerance by induction of a shift from a proinflammatory to an antiinflammatory immune response.
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Affiliation(s)
- Y Ilan
- Gastroenterology Unit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel
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